Neuropsychological follow-up in neonatal screening: issues, methods and findings

There are several ongoing studies of psychological outcome in children identified through neonatal screening with phenylketonuria, congenital hypothyroidism or congenital adrenal hyperplasia. These studies document the reduction in mental retardation, learning difficulties and behaviour problems associated with neonatal screening. They also describe other behavioural changes resulting from these disorders. Some behavioural changes are transient or preventable with early diagnosis and treatment, whereas some appear to be irreversible, reflecting permanent brain effects of abnormalities associated with the disease. Despite the variety of disorders studied, there are commonalities in approach and issues, including a developmental neuropsychological perspective resulting in behavioural assessments specific to the disorder and its likely manifestations, a recognition that behaviour may change across time in association with brain development and an understanding of the neural mechanisms underlying the behavioural changes. Assessments go beyond IQ, and include specific intellectual abilities, social behaviour, temperament, behaviour problems and identity. Behavioural changes are related to specific characteristics of the disease and its treatment, including the timing of exposure to abnormal hormones and/or neurotransmitters, the severity of the disease, and the age at initiation and adequacy of treatment. These studies provide information about the ways in which hormones and neurotransmitters affect the development and ongoing function of the brain, and an understanding of the ways in which neonatal screening results in improved psychological outcome. They also provide models for psychological follow-up of other disorders detected through neonatal screening.     

Neuropsychological follow-up in neonatal screening: issues, methods and findings

There are several ongoing studies of psychological outcome in children identified through neonatal screening with phenylketonuria, congenital hypothyroidism or congenital adrenal hyperplasia. These studies document the reduction in mental retardation, learning difficulties and behaviour problems associated with neonatal screening. They also describe other behavioural changes resulting from these disorders. Some behavioural changes are transient or preventable with early diagnosis and treatment, whereas some appear to be irreversible, reflecting permanent brain effects of abnormalities associated with the disease. Despite the variety of disorders studied, there are commonalities in approach and issues, including a developmental neuropsychological perspective resulting in behavioural assessments specific to the disorder and its likely manifestations, a recognition that behaviour may change across time in association with brain development and an understanding of the neural mechanisms underlying the behavioural changes. Assessments go beyond IQ, and include specific intellectual abilities, social behaviour, temperament, behaviour problems and identity. Behavioural changes are related to specific characteristics of the disease and its treatment, including the timing of exposure to abnormal hormones and/or neurotransmitters, the severity of the disease, and the age at initiation and adequacy of treatment. These studies provide information about the ways in which hormones and neurotransmitters affect the development and ongoing function of the brain, and an understanding of the ways in which neonatal screening results in improved psychological outcome. They also provide models for psychological follow-up of other disorders detected through neonatal screening.     

Endocrine disruption in sexual differentiation and puberty. What do pseudohermaphroditic polar bears have to do with the practice of pediatrics?

What do pseudohermaphroditic polar bears and girls with premature breast development have in common? Hormones. Sexual differentiation and the initiation of secondary sexual characteristics, such as breast growth, are both under the control of the sex hormones estrogen and androgen. Abnormal differentiation of the internal or external genitalia in bears and early onset of breast development in girls also may have a common element--exposure to environmental hormones.     

Early symptoms in autism from family home movies. Evaluation and comparison between 1st and 2nd year of life using I.B.S.E. scale.

The analysis of 11 home movies taken by parents before the recognition of autistic or atypical disorders of their own child has confirmed the major value of this method for describing early pathological signs. Symptomatology analysis has revealed anomalies of eye contact, a deficiency and variability of emotional expression, a defect of attention and initiation of communication, as well as motor abnormalities. The comparison of the frequency of abnormal behaviour, assessed with a rating scale among three groups of children (autistic, pervasive developmental disorders and normal) revealed behavioural differences as a function of early age and diagnosis, which concern not only social and communicative behaviours, but those of emotion and attention as well. The limits and interest of this methodological approach are discussed and the possibilities of subsequently using these documents in a more complete method, such as blind examination and scoring by uninformed investigators, are suggested.     

小青春期与性发育异常疾病早期诊断的研究进展

婴儿早期有一个短暂的下丘腩-垂体-性腺轴活性激增期,称为小青春期,此期体内诸多性激素水平呈特殊的分泌模式,是性发育的重要时期,可为临床医师早期诊断性发育异常疾病提供依据.该文主要综述小青春期的形成和特点,以及其激素分泌异常导致男性性发育异常的机制,从而探讨小青春期在性发育异常疾病早期诊断中的价值.     

小青春期与性发育异常疾病早期诊断的研究进展

婴儿早期有一个短暂的下丘腩-垂体-性腺轴活性激增期,称为小青春期,此期体内诸多性激素水平呈特殊的分泌模式,是性发育的重要时期,可为临床医师早期诊断性发育异常疾病提供依据.该文主要综述小青春期的形成和特点,以及其激素分泌异常导致男性性发育异常的机制,从而探讨小青春期在性发育异常疾病早期诊断中的价值.     

环境内分泌干扰物与儿童性分化、性发育异常

环境内分泌干扰物是普遍存在于环境中的一类外源性化学物质,这些物质可干扰体内天然激素的合成、释放、转运、与受体结合、代谢及清除等各个方面,干扰正常激素维持体内平衡和调节发育过程的作用.环境内分泌干扰物被证实是引起儿童性分化、性发育异常的重要致病因素.环境内分泌干扰物可扰乱下丘脑-垂体-性腺轴,干扰雄激素的生物合成、转运、...     

Fetal testosterone and sex differences

Experiments in animals leave no doubt that androgens, including testosterone, produced by the testes in fetal and/or neonatal life act on the brain to induce sex differences in neural structure and function. In this article, we argue that prenatal and neonatal testosterone exposure are strong candidates for having a causal role in sexual dimorphism in human behaviour, including social development.     

Sexual precocity with hypothalamic hypopituitarism.

Two girls, one with septo-optic dysplasia and the other with posttraumatic brain damage, had the unusual combination of human growth hormone, thyrotropin, adrenocorticotrophic hormone, and vasopressin deficiencies that were associated with sexual precocity in one patient and early sexual maturation in the second patient, and of adult follicle-stimulating hormone and luteinizing hormone concentrations. At autopsy, the first patient had optic nerve aplasia, a normal pituitary gland, and some disorganization of myelinated fibers in the hypothalamus. The second patient had a normal thyrotropin and prolactin response to thyrotropin-releasing hormone, plus hyperphagia, deranged thirst mechanism, and temperature instability. These findings suggest that the lesion may be a defective hypothalamic regulation of pituitary hormone secretion. Congenital or traumatic hypothalamic-pituitary lesions may not affect all releasing factors or trophic hormones in a similar fashion.     

Attention across modalities as a longitudinal predictor of early outcomes: the case of fragile X syndrome

Background: Fragile X syndrome (FXS) is an early diagnosed monogenic disorder, associated with a striking pattern of cognitive/attentional difficulties and a high risk of poor behavioural outcomes. FXS therefore represents an ideal model disorder to study prospectively the impact of early attention deficits on behaviour. Methods: Thirty‐seven boys with FXS aged 4–10 years and 74 typically developing (TD) boys took part. Study 1 was designed to assess visual and auditory attention at two time‐points, 1 year apart. Study 2 investigated attention to multimodal information. Both tested attention markers as longitudinal predictors of risk for poor behaviour in FXS. Results: Children with FXS attended less well than mental‐age matched TD boys and experienced greater difficulties with auditory compared to visual stimuli. In addition, unlike TD children, they did not benefit from multimodal information. Attention markers were significant predictors of later behavioural difficulties in boys with FXS. Conclusions: Findings demonstrate, for the first time, greater difficulties with auditory attention and atypical processing of multimodal information, in addition to pervasive global attentional difficulties in boys with FXS. Attention predicted outcomes longitudinally, underscoring the need to dissect what drives differing developmental trajectories for individual children within a seemingly homogeneous group.     

Low-level lead exposure and children

The adverse effects of environmental lead exposure on the mental development of young children are well established. There is no safe level of blood lead below which children are not affected. Recent research expands our understanding of the impact of lead exposure continuing into later childhood, as well as its effects on children's behaviour. However, social and other environmental factors also contribute to variance in measures of developmental and behavioural outcomes. Lead is associated with only modest effects on children's development, but is a potentially modifiable risk factor. As environmental exposure to lead declines for the whole population, continued specific attention is needed for children living in industrial areas.     

Second to fourth finger ratio and possible precursors of developmental psychopathology in preschool children

BACKGROUND: The influence of sex steroids upon brain development has been suggested to mediate sex differences in developmental psychopathology. The ratio of the length of index finger or second finger to the ring finger or fourth finger (the 2D:4D ratio) appears to be a marker of early sex hormone exposure, with low 2D:4D associated with high prenatal testosterone and high 2D:4D associated with high prenatal oestrogen. This relationship allows a non-invasive measure of the long-term influence of prenatal sex steroids. Behaviours such as hyperactivity and poor social cognition are common in preschoolers. An association between 2D:4D and these possible precursors of psychopathology would be most readily identified in this group. AIM: To identify relationships between 2D:4D ratio and behaviours in preschool children which constitute possible precursors of developmental psychopathology. STUDY DESIGN: Population survey. METHOD: The 2D:4D ratio was measured in a group of preschool children and behavioural questionnaires were given to parents and teachers. RESULTS: Sex differences in behaviours were small, whilst correlations with 2D:4D were strong. Low 2D:4D was related to hyperactivity and poor social cognitive function in girls, and high 2D:4D with emotional symptoms in boys. CONCLUSIONS: We suggest that during early brain development androgens increase the probability of hyperactivity and poor social cognition in girls. Early oestrogens increase the probability of emotional problems in boys.     

Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016)

Kung et al. (2016) contribute further evidence demonstrating no clear link between prenatal androgen exposure and the autism phenotype. Do these findings represent a nail in the coffin for the extreme male brain (EMB) theory of autism, or are we simply asking too much of the hypothesis? This commentary highlights the inconsistent findings that have appeared to undermine the EMB theory, but presents an argument that the data may not present an adequate test of the hypothesis. A research agenda is then outlined – the investigation of simple behavioural traits rather than the full combination of ASD behaviours – which may provide greater clarity as to how prenatal androgen exposure relates to developmental psychopathology.     

Iodine deficiency and development of brain

Iodine is a trace element essential for the synthesis of triodothyronine (T₃) and thyroxine (T₄). Inadequate intake of iodine leads to insufficient production of these hormones, which play a vital role in the process of early growth and development of most organs, especially the brain. The neurological sequele of iodine deficiency are mediated by thyroid hormone deficiency, varying from minimal brain function to a syndrome of severe intellectual disability. All the basic processes of neurogenesis: cellular proliferation, differentiation, migration, and selective cell death are impaired during period of brain growth spurt. Evidence suggests alterations in synaptology, neurons, myelin sheaths, glial cells, and morphology of cerebrum and cerebellum in severe iodine deficiency. Foetal thyroid ontogenesis occurs after the first trimester. Until then foetus is dependent on maternal T₄. A thyroid dependent event important for subsequent brain development occurs in the beginning of the third trimester of pregnancy     

Effects on later adjustment of living in a stepfamily during childhood and adolescence

This paper examines the effects of living in a stepfamily during childhood and adolescence on a range of psychosocial outcomes at age 18 years. Data collected during an 18-year longitudinal study were used to examine a sample of 907 children with respect to: exposure to living in a stepfamily during the period from age 6 to 16 years; measures of psychosocial outcomes including mental health, antisocial behaviour, substance use, restricted life opportunities, and sexual risk-taking at age 18 years; and measures of prospectively collected confounding factors. The analyses revealed that children exposed to living in a stepfamily for the first time between ages 6-16 years had elevated risks of a range of psychosocial outcomes at 18 years. These included elevated risks of: (1) juvenile offending; (2) nicotine dependence; (3) abuse or dependence on illicit substances; (4) leaving school without qualifications; (5) early onset of sexual activity; and (6) multiple sexual partners. However, these risks were reduced substantially when psychosocial outcomes were adjusted for the confounding effects of antecedent factors such as: family socioeconomic characteristics: family history of instability, adversity, and conflict; mother's age, religiosity, and smoking; child gender; and preexisting child conduct and attentional problems. After adjustment, the odds ratios between exposure to a stepfamily and adolescent outcomes were nonsignificant. Additional analysis revealed that there were no significant differences in outcomes for boys and girls exposed to stepfamilies. It was concluded that although young people exposed to living in a stepfamily had increased risks of poor psychosocial outcomes, much of this association appeared to be spurious, and arose from confounding social, contextual, and individual factors that were present prior to the formation of the stepfamily.     

Dietary change mediates relationships between stress during pregnancy and infant head circumference measures: the QF2011 study

Prenatal maternal stress can adversely affect birth outcomes, likely reflecting effects of maternal stress hormones on fetal development. Maternal stress might also induce behavioural changes, such as dietary change, that might influence fetal development. Few studies have documented relationships between stress and dietary change in pregnancy. We analysed stress and dietary change among 222 pregnant women exposed to the 2011 Queensland Floods. We assessed women's objective hardship, subjective distress and cognitive appraisal of the disaster; changes in their diets and their associations with infants' gestational age, weight, length and head circumference at birth, head circumference to birth length ratio (HC/BL) and ponderal index. Greater objective hardship was correlated with more negative dietary change, skipped meals and skipped multivitamins. There were no direct effects of stress or dietary change on birth outcomes. However, we observed an interactive effect of dietary change and exposure timing on head circumference for gestational age (HC for GA) (p = 0.010) and a similar trend for HC/BL (p = 0.064). HC for GA and HC/BL were larger among children whose mothers experienced negative changes to their diet in early pregnancy compared with later pregnancy, consistent with a ‘head‐sparing’ response with early gestation exposure. Further analyses indicated that dietary change mediates the relationship between objective hardship because of the floods and these outcomes. This is the first report of relationships among an independent stressor, dietary change and birth outcomes. It highlights another possible mechanism in the relationship between prenatal maternal stress and child development that could guide future research and interventions.     

Effects of short-course androgen therapy on the neurodevelopmental profile of infants and children with 49,XXXXY syndrome

Aim: The aim of this investigation was to ascertain whether an early course of androgen treatment (three injections testosterone enanthate, 25 mg) could have a positive impact on any domains of neurodevelopmental function in boys with 49,XXXXY. Methods: A total of 22 boys with a karyotype of 49,XXXXY participated in a multidisciplinary assessment of neurocognition, speech and language, paediatric neurology and endocrinology evaluations. One group had received early androgen and another group did not receive any hormonal treatment prior to the evaluation. The mean age of treatment for Group 1 was 12 months with the mean age of first evaluation 74 months. The mean age of first evaluation for Group 2 was 87 months. Statistical analysis was completed to determine whether there was a positive treatment effect from androgen therapy. Results: There was a significant positive treatment effect in speech and language domain, gestural communication and vocabulary development. No treatment effect was seen on nonverbal capacities. Conclusion: Our findings revealed improved function in several areas of development which had been severely delayed in boys with 49,XXXXY. Continued research is underway to expand our understanding of the relationship of androgen, brain function and behavioural outcome in boys with 49,XXXXY.     

Melatonin and sex hormone interrelationships--a review

Melatonin, the main hormone secreted by the pineal gland at night, plays a major role in regulating reproductive physiology in seasonal breeders and influences the age of sexual maturation in laboratory rodents. In humans these relationships are less clear. Evidence supporting a melatonin-reproductive hormone relationship relies on findings of abnormal melatonin secretion in disorders of the reproductive system and on pathologies of the pineal gland which are associated with clinical abnormalities of the reproductive hormones. Normal melatonin rhythms are closely related to those of the reproductive hormones during infancy and reciprocally correlated during puberty. The demonstration of melatonin receptors in the brain and in reproductive organs, together with the localization of sex hormone receptors in the pineal gland, further strengthen these relationships. However, it is not yet clear that these correlations are functionally related, as data on the antigonadal effects of exogenous melatonin on the reproductive hormones are not conclusively established.     

Health and behaviour problems at 8 weeks as predictors of behaviour problems at 8 months.

OBJECTIVE: To assess the value of health and behavioural problems at 8 weeks as predictors of behavioural problems at 8 months in a whole year birth cohort. STUDY DESIGN: Prospective birth cohort study. SETTING: The socially and ethnically diverse city of Coventry. MAIN OUTCOME: Parent reported behavioural problems at 8 months. METHOD: Parent reported infant health and behaviour data were collected, using a validated questionnaire administered by the family health visitor at 8 weeks and 8 months, on 1541 infants participating in the Coventry cohort study. Sociodemographic data were collected at the health visitor's initial visit. Unadjusted relative risks (with 95% confidence intervals (CI)) of behaviour problems at 8 months by sociodemographic variables and health and behavioural problems at 8 weeks were estimated. Adjustment for confounding was made by logistic regression. RESULTS: Infants reported to have behavioural problems at 8 weeks had a significant risk of parent reported behavioural problems at 8 months (adjusted relative risk, 3.44; 95% CI, 1.95 to 6.09) after adjustment for other health outcomes and sociodemographic factors. Of infants with behavioural problems by 8 weeks of age, 19.1% were reported to have behavioural problems at 8 months. CONCLUSIONS: Infants whose parents report behaviour problems by 8 weeks of age are at higher risk of behavioural problems at 8 months. However, despite the higher risk, the proportions of infants identified by behaviour at 8 weeks were too small for the early outcomes to be useful as predictors of behaviour at 8 months in the whole infant population.